This invention relates to a novel mechanism of neuropsychiatric intervention. More particularly, this invention is directed to pharmaceutical formulations and methods for treatment of a variety of peptidase mediated disease states, including cognitive and behavioral disorders.
The pharmaceutical industry has directed extensive research and development efforts toward discovery and commercialization of drugs for treatment of neurological disorders. Such disorders typically derive from chemical imbalances in the brain. Overproduction or underproduction of pertinent neurochemical species and/or receptor dysfunction has been identified with many disease states recognized by neurologists, psychiatrists, psychologists and other medical practitioners skilled in the diagnosis and treatment of mental disease. Most of the discovery effort for new neurologically active drugs has been based on the study of agonist/antagonist drug interaction with one or more of the numerous receptors in the brain and/or their respective receptor ligands.
The present invention provides a novel approach to drug intervention in the treatment of a wide variety of neurologic disease states and other disease states or clinical conditions of related etiology. It is based in part on the discovery that xcex2-lactam containing compounds known for their activity as inhibitors of bacterial peptidases or proteases, particularly transpeptidases and/or carboxypeptidases, are also potent inhibitors of certain mammalian peptidases generically referred to as N-acetylated-xcex1-linked acidic peptidases (NAALADases), several of which have been identified/characterized in the literature [Pangalos et al., J. Biol. Chem., 1999, 274, No. 13, 8470-8783]. The present invention is also based in part on the discovery that neurogenic NAALADases can be targeted with NAALADase inhibitors to effect significant behavioral modification and enhanced cognitive performance. Preliminary studies have confirmed that one or more neurogenic proteases, now believed to be NAALADases, capable of recognizing and transforming certain neuropeptides (e.g., N-acetyl-L-aspartyl-L-glutamate) play a significant if not dominant role at the neurochemical level of brain function and concomitantly have a substantial impact on patient behavior and cognitive performance. It has been previously reported that certain glutamate analogs acting as NAALADase inhibitors can be used to treat prostate disease and glutamate abnormalities associated with certain nervous tissue insult. It has now been determined that NAALADase inhibitors, including particularly certain bacterial peptidase and xcex2-lactamase inhibitors capable of blood-brain barrier transport, can function in the brain at very low concentrations as potent neuroactive drug substances to reduce the symptoms of a wide variety of neurological disorders characterized by behavioral aberration or cognitive dysfunction. Significantly such bacterial enzyme inhibitors are believed to be effective NAALADase inhibitors at concentrations below those concentrations known to be required for clinically effective bacterial peptidase inhibition. Thus they can also be used effectively for treating prostate disease and the disease states associated with nervous tissue insult previously described as responsive to treatment with NAALADase inhibitors.
Accordingly, one embodiment of the present invention is directed to a method for treatment of cognitive and behavioral disorders in warm-blooded vertebrates by administering compounds known for their activity as bacterial protease or peptidase inhibitors, which compounds, when present at effective concentrations in the brain, have now been determined to be capable of inhibiting or otherwise modulating the activity of one or more neurogenic NAALADases.
In a related embodiment there is provided method for treatment of cognitive and behavioral disorders in a patient in need of such treatment. The method comprises the step of inhibiting neurogenic NAALADase activity. In one embodiment such neuropeptidase inhibition is effected by administering an effective amount of a xcex2-lactam compound recognized for its capacity to bind to and inhibit a bacterial enzyme, for example, a xcex2-lactamase or a bacterial protease involved in bacterial cell wall synthesis and exhibiting selective proteolytic activity on bacterial peptidoglycans. Such bacterial proteases are known in the art as xe2x80x9cpenicillin binding proteins.xe2x80x9d In another embodiment of the present invention, the method is effected by administration of art-recognized NAALADase inhibitors, including particularly certain deaminoglutamate analogues and N-substituted glutamate derivatives. Effective inhibition of such neuro-peptidase activity in warm-blooded vertebrates has been found to produce marked enhancement in cognitive performance and behavioral management.
Exemplary of cognitive and behavioral disorders susceptible to treatment in accordance with this invention include aggressive disorder, obsessive compulsive disorder, anxiety, depression, ADHD, and memory impairment. Animal data suggest that the method and formulation of this invention have potential as an antiaggressive agent to control impulsivity and violence in autism, Tourette""s syndrome, mental retardation, psychosis, mania, senile dementia and individuals with personality disorders and history of inappropriate aggression. Clinic applications extend to the treatment of children with ADHD and conduct disorder, as an anxiolytic, and as a cognition enhancer for the geriatric population to improve learning and memory and to ameliorate disorientation.
In another embodiment of this invention there is provided a method of treating a patient afflicted with a condition, or disposed to development of a condition, characterized at least in part by abnormal extracellular concentration of glutamate in the brain or other nervous tissue. The method comprises the step of administering to the patient in effective amounts of a compound capable of inhibiting the activity of a penicillin-binding protein of bacterial origin. The composition is administered in an amount effective to prevent or alleviate the symptoms of such condition. Thus, for example, localized high glutamate concentrations in the brain have been reported in stroke victims and victims of other brain trauma. More recently high glutamate concentrations in the brain and peripheral nerve tissue have been reported to be associated with multiple sclerosis.
In still another embodiment of the invention there is provided a method for treating prostate disease selected from prostate cancer and benign prostate hyperplasia in a human patient. The method comprises the step of administering to the patient a composition comprising a compound capable of inhibiting the activity of a penicillin-binding protein of bacterial origin. The compound is administered in an amount effective to retard the progress of the disease or to reduce the symptoms of the disease.
One group of compounds for use in accordance with this invention are xcex2-lactam compounds, i.e., compounds having a xcex2-lactam ring system, including particularly xcex2-lactam antibiotics such as penicillins, cephalosporins and analogues thereof. In one preferred embodiment the xcex2-lactam compound is clavulanic acid and pharmaceutically acceptable derivatives thereof. Further, the peptide Ala-D-xcex3-Glu-Lys-D-Ala-D-Ala (believed to serve as a substrate for NAALADase) has been found effective as a peptidase inhibitor useful for behavior modification and cognitive/sensory enhancement in accordance with the invention. Non-xcex2-lactam NAALADase inhibitors have been reported in the patent and non-patent literature. See, e.g., U.S. Pat. Nos. 5,795,877; 5,804,602; 5,968,915; 5,902,817; 5,962,521 and 5,863,536, the specifications of which are specifically incorporated herein by reference for their teaching of such NAALADase inhibitors and the use generally of such NAALADase inhibitors for treatment of certain disease states responsive to NAALADase inhibition therapy. Other compounds capable of use in accordance with this invention can be identified using molecular modeling studies. The antibiotic compounds for use in this invention can be administered in combination with one or more of other enzyme inhibitors, for example, effective amounts of a xcex2-lactamase inhibitor (where the active compound is a xcex2-lactam) or another NAALADase inhibitor or a P-glycoprotein efflux inhibitor to enhance brain levels of the active compound. The method and formulation embodiments of the invention find use in both human health and veterinary applications, e.g., in canine, feline and equine species.
In one embodiment a warm-blooded vertebrate, most typically a human patient, affected by a neurologic disease state characterized by cognitive or behavioral abnormalities is treated with a 1-oxa-1-dethia cephalosporin, more preferably a 7-methoxy-1-oxa-1-dethia cephalosporin, optionally as an active ester derivative in an orally (including buccal or sublingual administration) or a parenterally administered formulation. In one embodiment, the peptidase inhibitor is moxalactam, [7-xcex2-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7xcex1-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid], described and claimed with related compounds, including their orally absorbed active ester derivatives, in U.S. Pat. No. 4,323,567, the specification of which is expressly incorporated herein by reference. Moxalactam has been found to exhibit significant dose responsive neuroactivity when administered parenterally at least at about 50 xcexcg/kg of body weight. Clavulanic acid has also been found to exhibit dose responsive neuroactivity when administered at levels as low as 10 ng/kg.
In another embodiment of the present invention there is provided a pharmaceutical formulation for treatment with consequent reduction of symptoms of behavioral or cognitive disorders in patients in need of such treatment. The formulation comprises a compound characterized by its affinity to bacteria derived penicillin-binding proteins. In one embodiment the compound is capable of binding to and inhibiting the function of a bacterial protease known to exhibit its proteolytic activity on a peptidoglycan substrate comprising the C-terminal peptide sequence acyl-D-alanyl-D-alanine. In one preferred embodiment the compound is capable of binding to xcex2-lactamase, another bacterial protein capable of binding to penicillin, and inhibiting the function of that enzyme. The amount of the inhibitor used in the formulation is that determined to be effective to inhibit the activity of endogenous NAALADase. In one embodiment the amount is effective to inhibit NAALADase in the brain at a level sufficient to modulate cognitive and behavioral characteristics. In that later embodiment the level of activity exhibited by the NAALADase inhibitor in the present method is not only dependent on its affinity to penicillin-binding proteins and to NAALADase, it is also particularly dependent on ability of the inhibitor compound to cross the blood brain barrier to achieve levels in the brain effective to modify patient behavior and/or cognitive performance. Clavulanic acid and formulations thereof have been found to exhibit the most robust neurologic activity, presumptively due to its high bioavailability, its good blood brain transport, and its apparent high affinity to NAALADase and probably other structurally related neurogenic peptidases.
In one embodiment of the invention the pharmaceutical formulation comprises a xcex2-lactam containing compound selected from the group consisting of penicillin, cephalosporins, xcex2-lactam containing analogues thereof, including xcex2-lactamase inhibitors, and a pharmaceutical carrier for such xcex2-lactam containing compound. In cases where the xcex2-lactam compound is, for example, a commercially available antibiotic, the amount of xcex2-lactam compound in said formulation is less than that required to produce, upon administration by the commercially detailed mode of xcex2-lactamase inhibitors, and a pharmaceutical carrier for such xcex2-lactam containing compound. In cases where the xcex2-lactam compound is, for example, a commercially available antibiotic, the amount of xcex2-lactam compound in said formulation is less than that required to produce, upon administration by the commercially detailed mode of administration, clinically effective antibiotic blood levels of the compound. Yet the reduced dosage levels of said antibiotics can be effective, assuming reasonable blood-brain barrier transport properties, to produce brain and CSF levels of the compound sufficient to inhibit neurogenic protease (NAALADase) activity in the brain and modify cognitive and behavioral characteristics. Such formulations can optionally include, in addition, effective amounts of one or more of a xcex2-lactamase inhibitor and a P-glycoprotein efflux pump inhibitor or another compound capable of inhibiting the activity of NAALADase and related neurogenic enzymes. In one preferred embodiment the formulation comprises clavulanic acid or a pharmaceutically acceptable salt or active ester form thereof, and a pharmaceutically acceptable carrier wherein the formulation is free of any clinically effective xcex2-lactam antibiotic. While the formulations of this invention can be prepared specifically for any art-recognized mode of administration capable of achieving threshold minimum protease inhibiting concentrations in the brain, they are typically formulated for parenteral or oral administration, optionally in the form of prolonged release or xe2x80x9cdrug depotxe2x80x9d type formulations well known in the art.